This project was initiated to fill a void in our knowledge regarding the neurobiological substrates of the the adverse effects of chronic marijuana use on cognition in humans. It is well-known that both acute and chronic marijuana use in humans impairs short-term memory, reaction times, and general higher-order cognitive processing. These studies seek to utilize animal models to explore the effects of both acute and chronic exposure to the main psychoactive ingredient in marijuana, delta9-tetrahydrocannabinol (THC) on the neurophysiology of the hippocampus and now the ventral tegmental area (VTA). Our prior published study showed that repeated injections of THC blocked long-term potentiation (LTP), a cellular correlate of learning and memory. Furthermore, a single injection of THC was insufficient to block LTP, the LTP blockade persisted for 3d after the last THC injection, and it was prevented by pretreatment of the animals before each THC injection with the antagonist AM251 (2 mg/kg). We are also defining the actions of acute THC exposure on individual neurons in hippocampal brain slices using whole-cell recordings. The majority of studies to date have utilized synthetic CB agonists to assess the role of CB1 receptors in modulating hippocampal synaptic function. By comparing the effects of THC to those of these synthetic agonists, we hope to identify putative molecular targets of THC that may help explain memory impairments in humans following chronic marijuana use. Our most recent work has found that whereas THC acts as a partial agonist in the inhibition of glutamate release in the hippocampus, it is a full agonist when its effects are measured on the inhibition of GABA release in the hippocampus. We believe that this difference is due to a much higher CB1 receptor density on GABAergic axon terminals versus glutamate terminals in this brain structure, and we have proposed that this provides strong evidence that the primary site of THC's interaction to disrupt hippocampal-dependent memory is on GABAergic systems. In a separate study, we have reported that the effects of cannabinoids on hippocampal glutamate release can be greatly potentiated when adenosine A1 receptors are blocked. This suggests that endogenous adenosine is involved in regulating the strength of signaling through CB1 receptors in the hippocampus, and that endocannabinoid function is under control of the adenosine system. This is important because it is well known that the neuromodulator, adenosine, is released during periods of cellular and metabolic stress, and that it plays an important role in terminating seizures. Therefore, we predict that the conditions that regulate adenosine release will also modify the effects of endogenous cannabinoids, and the effects of marijuana in the hippocampus. Current experiments are involved in defining the source and site of action of endogenous adenosine in the hippocampus, with the ultimate goal of identifying how adenosine A1 receptors and endogenous adenosine interfere with cannabinoid receptor signaling. Preliminary data indicate that endogenous adenosine are released from mossy fibers in in area CA3 and this is inhibiting impulse activity in CA3 neuron axons that express cannabinoid CB1 receptors in area CA1. Through this mechanism we hypothesize that endogenous adenosine released during states of high metabolic demand can regulate the functions of endogenous cannabinoids and THC in area CA1 of the hippocampus. Ultimately, this will affect cognition, mood and learning by disrupting hippocampal function. An additional pertinent observation from these studies is that the commonly consumed substance, caffeine, which is available in many forms, can increase the ability of marijuana to disrupt hippocampal function. This could have important implications for the developing brain, either in utero, before birth, or in the adolescent brain. Relevant public health concerns may therefore involve the use of marijuana and beverages containing high levels of caffeine in adolescents, and the adverse cognitive and neurodevelopmental consequences.